Anti-endotoxin compounds

Abstract

Disclosed are lipid A analogs useful for the treatment of septic shock and LPS-mediated activation of viral infection.

What is claimed is: 
     
       1. A compound of formula: ##STR290## wherein R 2  is: ##STR291## wherein each J, independently, is OH or a protected OH; each L is O, N, or C; each M is O or N; each E, independently, is an integer between 0 and 14 inclusive; each m, independently, is an integer between 0 and 14 inclusive; each n, independently, is an integer between 0 and 14 inclusive; each p, independently, is an integer between 0 and 10 inclusive; each q, independently, is an integer between 0 and 10 inclusive; each x, independently, is an integer between 0 and 14 inclusive; each y, independently, is an integer between 0 and 14 inclusive; each z, independently, is an integer between 0 and 10 inclusive; and each G, independently, is N, O, S, SO, or SO 2  ; P 1  is OH, a protected OH, or a protected A 1  group wherein each A 1  group, independently, is: ##STR292## wherein each d, independently, is an integer between 0 and 5 inclusive; each f, independently, is an integer between 0 and 5 inclusive; each g, independently, is an integer between 0 and 5 inclusive; and each A 3 , independently, is: ##STR293##   (CH.sub.2).sub.j --CO.sub.2 H, or O--(CH.sub.2).sub.j --CO.sub.2 H     wherein each j, independently, is an integer between 0 and 14 inclusive; and     P 2  is H, a halo group, OH, a protected OH, O(CH 2 ) w  CH 3 , ##STR294## wherein w is an integer between 0 and 14 inclusive, or a pharmaceutically acceptable salt thereof.   
     
     
       2. The compound of claim 1, wherein R 2  is: ##STR295## wherein each J, independently, is OH or a protected OH; each m, independently, is an integer between 0 and 10 inclusive; each n, independently, is an integer between 0 and 10 inclusive; each x, independently, is an integer between 0 and 10 inclusive; each z, independently, is an integer between 0 and 3 inclusive; each G, independently, is SO or SO 2  ; and for each p and q, independently,   ≦ (p+q)≦12;     P 1  is OH, a protected OH, or a protected A 1  group wherein each A 1  group is: ##STR296## wherein each d, independently, is an integer between 0 and 2 inclusive; and   P 2  is H, OH, a protected OH, or O(CH 2 ) w  CH 3 , wherein w is an integer between 0 and 3 inclusive.   
     
     
       3. The compound of claim 2, wherein R 2  is ##STR297## wherein each J, independently, is OH or a protected OH; each x, independently, is an integer between 6 and 11 inclusive; each G, independently, is SO or SO 2  ; each n, independently, is an integer between 6 and 10 inclusive; and   ≦ (p+q)≦10;     P 1  is ##STR298## and P 2  is H, OH, a protected OH, or OCH 3 .   
     
     
       4. A compound of the formula: ##STR299## wherein R 4  is ##STR300## wherein each J, independently, is OH or a protected OH; L is O, N, or C; each M is O or N; each E, independently, is an integer between 0 and 14 inclusive; each m, independently, is an integer between 0 and 14 inclusive; each n, independently, is an integer between 0 and 14 inclusive; each p, independently, is an integer between 0 and 10 inclusive; each q, independently, is an integer between 0 and 10 inclusive; each x, independently, is an integer between 0 and 14 inclusive; each y, independently, is an integer between 0 and 14 inclusive; each z, independently, is an integer between 0 and 10 inclusive; and each G, independently, is N, O, S, SO, or SO 2  ; Z is OH, a protected OH, an activated OH, or a displacable leaving group;   P 3  is OH, a protected OH, OCH 3 , A 2' , or a protected A 2' , wherein said A 2'   group is: ##STR301## wherein each d, independently, is an integer between 0 and 5 inclusive; each f, independently, is an integer between 0 and 5 inclusive; each g, independently, is an integer between 0 and 5 inclusive; and each A 3 , independently, is: ##STR302##   (CH.sub.2).sub.j --CO.sub.2 H, or O--(CH.sub.2).sub.j --CO.sub.2 H     wherein each j, independently, is an integer between 0 and 14 inclusive;     X' is X or a protected X group, wherein said X group is H, (CH 2 ) t  CH 3 , (CH 2 ) t  OH, (CH 2 ) t  O(CH 2 ) v  CH 3 , (CH 2 ) t  OPO(OH) 2 ,   (CH.sub.2).sub.t --CH═CH--(CH.sub.2).sub.v CH.sub.3, (CH.sub.2).sub.t --O--R.sup.5, ##STR303## wherein each t and v, independently, is an integer between 0 and 14 inclusive; and R.sup.5 is any of the possibilities listed above for R.sup.1 -R.sup.4, or a pharmaceutically acceptable salt thereof.       
     
     
       5. The compound of claim 4 wherein R 4  is: ##STR304## wherein each J, independently, is OH or a protected OH; each m, independently, is an integer between 0 and 10 inclusive; each n, independently, is an integer between 0 and 10 inclusive; each x, independently, is an integer between 0 and 10 inclusive; each z, independently, is an integer between 0 and 3 inclusive; each G, independently, is SO or SO 2  ; and for each p and q, independently,   ≦ (p+q)≦12;     each P 3  is H, OH, a protected OH, A 2'   or protected A 2' , wherein A 2'   is ##STR305## wherein each d, independently, is an integer between 0 and 2 inclusive; and   X' is H, (CH 2 ) t  OH, (CH 2 ) t  O(CH 2 ) v  CH 3  or (CH 2 ) t  CH 3 , wherein t is an integer between 0 and 6 inclusive and v is an integer between 0 and 6.   
     
     
       6. The compound of claim 5, wherein R 4  is ##STR306## wherein each J, independently, is OH or a protected OH; each x, independently, is an integer between 6 and 11 inclusive; and each G, independently, is SO or SO 2  ; each n, independently, is an integer between 6 and 10 inclusive; and   ≦ (p+q)≦10;     P 3  is OH, a protected OH, A 2' , or a protected A 2' , wherein A 2'   is ##STR307## and X' is CH 2  OH, CH 2  OCH 3 , or CH 2  O(CH 2 ) v  CH 3 , wherein v is an integer between 1 and 3 inclusive.